ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson's disease

Mitochondrion. 2014 Jul:17:132-40. doi: 10.1016/j.mito.2014.04.008. Epub 2014 Apr 24.

Abstract

Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, which is downregulated by extracellular signal-regulated protein kinases (ERK1/2) in cells treated chronically with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+). We utilized mass spectrometry to identify ERK1/2-dependent TFAM phosphorylation sites. Mutation of TFAM at serine 177 to mimic phosphorylation recapitulated the effects of MPP+ in decreasing the binding of TFAM to the light strand promoter, suppressing mitochondrial transcription. Mutant TFAM was unable to affect respiratory function or rescue the effects of MPP+ on respiratory complexes. These data disclose a novel mechanism by which ERK1/2 regulates mitochondrial function through direct phosphorylation of TFAM.

Keywords: MAP kinases; Mitochondrial biogenesis; Parkinson disease; Phosphorylation; mtDNA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Mass Spectrometry
  • Mitochondria / chemistry
  • Mitochondria / genetics*
  • Mitochondrial Proteins / metabolism*
  • Parkinson Disease / physiopathology*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Transcription Factors / metabolism*
  • Transcription, Genetic*

Substances

  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • TFAM protein, human
  • Transcription Factors
  • Extracellular Signal-Regulated MAP Kinases